It has been estimated that ˜40% of emerging small molecule drugs have poor aqueous solubility and a short circulation half-life and require the development of effective drug formulations to improve their pharmacokinetics, biodistribution, toxicity profile and efficacy. When administrated intravenously, nanoscopic carriers offer the added advantage of concentrating in tumor tissues via the enhanced permeation and retention (EPR) effect defined by leaky vasculature and poor lymphatic drainage commonly seen in solid tumors. Studies have shown that following extravasation into tumor interstitium, a drug or drug-encapsulated vehicle should be capable of transport up to 100 μm away from the tumor vasculature in order to reach all cells within the tumor. There is increasing evidence that a drug's limited penetration and distribution within a tumor, which results in insufficient elimination of malignant cells, may contribute to tumor re-population after treatment. Current FDA approved DOXIL™ (˜100 nm) and ABRAXANE™ (˜130 nm), although highly promising, have provided only modest survival benefits. This is attributed to inefficient transport of the chemotherapeutic drug into the tumor due to their relatively larger size and drug leakage during blood circulation. Physiological factors, including the density and heterogeneity of the vasculature at the tumor site, interstitial fluid pressure, and transport of carriers in the tumor interstitium, impact the extent of extravasation of nanocarriers into tumors. Further, nanocarriers need to be below a certain size to achieve significant penetration where the range of nanocarrier diameter for efficient tumor penetration depends on the shape, hardness and architecture of the carrier. Recent studies using a human melanoma xenograft model in mice showed that smaller particles, i.e. 10-12 nm quantum dots, can more effectively penetrate the physiological barriers imposed by abnormal tumor vasculature and dense interstitial matrix than 60 nm nanoparticles. Using dendrimers, the physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumor microvasculature is approximately 12 nm. Organic nanoparticles based on elastin-like peptides, ˜25 nm in size, produced a nearly complete tumor regression in a murine cancer model.
The effectiveness of a drug carrier also depends on its stability and drug retention in vivo. To ensure an improvement in the toxicity profile of the drug, the drug needs to be retained within micelles until reaching the target site. In addition to enhanced cargo stability and tumor penetration, an equally important requirement for effective nanocarriers is the balance of stable circulation and nanocarrier clearance. Nanocarriers initially must be larger than 6 nm to achieve extended circulation lifetime and subsequently need to disintegrate into materials smaller than ˜6 nm or 50K Da in molecular weight to be eliminated from circulation by glomerular filtration in the kidney. The generation of organic nanocarriers in the size range of 10-30 nm which combine a long circulation half-life, effective tumor tissue penetration, minimal cargo leakage, and efficient subunit clearance remains a significant challenge.
Thermodynamically, the particle size is determined by the balance between interfacial interactions between the particle surface and the local medium and the cohesive energy stored in the particle. The surface area to volume ratio is inversely proportional to the particle size. As the particle size reduces down to the nanoscale, low surface tension of the particle surface and/or high cohesive energy density within nanoparticles are needed to stabilize individual nanoparticles. Depending on the amount of chemical energy involved in the formation and stabilization of nanoparticles, current organic nanoparticles can be divided into two categories. In one family of nanoparticles, including dendrimers, subunits are bound together via covalent bonds, with a typical energy of a few tens of kcal per mole. The second family of organic nanoparticles is stabilized via non-covalent bonds, typically a few kcal per mol. These nanoparticles often have very low interfacial interactions since the energy stored in the particle is relatively low.
The kinetic stability of organic nanoparticles determines the in vivo stability, circulation half-life and clearance pathway. Covalent nanoparticles are often stable under common biological conditions until chemical degradation of covalent bonds occurs via external stimuli such as pH, temperature, light and enzymes. For non-covalent nanoparticles, however, the subunit can exchange with local medium or among particles. The kinetic energy barrier of the exchange decreases as the micelle size reduces, especially when the size is below 20 nm. Small micelles are generally fluid, dynamic assemblies, where the subunit amphiphiles are constantly exchanging with the surrounding media and with other micelles. The presence of chemical traps in vivo that stabilize individual amphiphiles further reduces the stability of micelles and leads to undesirable cargo leakage and disassembly. Chemically crosslinking the headgroups and/or engineering multiple pairs of intermolecular interactions among the headgroups can be effective to obtain stable micelles. However, biodistribution studies indicated accumulation in the liver and spleen and raised concerns over the potential long term toxicity.
Accordingly, an unmet need exists for small (i.e. on the order of a few tens of nanometers), stable micelles that can be assembled from convenient materials and used for in vivo delivery of drugs and other cargo. Surprisingly, the present invention addresses this and other needs.